CARCINOMA OF GALLBLADDER new management.pptx

Car cinoma of gall bladder management and

1. DEPARTMENT OF GENERAL SURGERY THE OXFORD MEDICAL COLLEGE, HOSPITAL AND RESEARCH CENTRE, BENGALURU Friday,JULY 12,2024

2. CARCINOMA OF GALL BLADDER DATE : 1 2 /7/2024 PRESENTER : DR. TANMAY CHAIR PERSONS: DR . SUSHIL KUMAR B.V. (HOD, DEPARTMENT OF GENERAL SURGERY) MODERATOR DR RAVISHANKAR S Friday,july12,2024 Department of General Surgery, TOMCH, Bengaluru 2

3. Topic outline: Anatomy Risk features Pathology Clinical features Diagnosis Staging Management Follow-up

4. Anatomy

5. Gallbladder - Partially intraperitoneal structure. Attached to undersurface of liver segment IVB and V. Cystic plate : On the side of gallbladder that is attached to liver, there is no peritoneal covering instead a fibrous lining known as cystic plate occupies this space. Parts : neck, infundibulum, Hartmann pouch, body and fundus. Bile is drained into CBD via cystic duct.

6. First draining nodal basin → Cystic and Pericholedochal nodes. Primary drainage areas - Retroportal and Pancreaticoduodenal nodes. Later - Celiac, Superior mesenteric, and finally to Aortocaval nodes.

7. EPIDEMIOLOGY

8. Gallbladder cancer (GBC) is the fifth most common malignancy of the GI tract. Age- >65 years. Incidence of gallbladder cancer : 1)Chilean Mapuche Indian women (27.3 cases/100,000 persons annually), Mortality-5.2% 2)Women living in India (22 cases per 100,000 persons annually), Source- Blumgart’s Surgery of the Liver, Biliary Tract, and Pancreas

9. Unique geographical distribution in river basin zones of Ganga-Meghna-Brahmaputra (GMB) plain. Population-based cancer registry (PBCR) data from India: 1)Highest incidence - Kamrup district (Assam), 2)16.2 / 100,000 - Women 3) 7.9 / 100,000 - Men

10. Risk of incidence of GBC : 7 times higher in the north and north-eastern states as compared with the south ( 8.6–17.1 in north/north-eastern PBCRs vs 0.7–4.1 in southern PBCRs/100,000) Top 5 incident areas : Kamrup , Cachar and Dibrugarh districts in Assam, Papumpare district in Arunachal Pradesh Imphal Dutta EK, Lewis MG, Albert S. Risk factors associated with gall bladder cancer in high incidence areas in India: a systematic review protocol. BMJ Open 2022;12:e056849. doi:10.1136/ bmjopen-2021-056849

11. Sources- 1) Blumgart’s Surgery of the Liver, Biliary Tract, and Pancreas 2)DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology (Cancer Principles and Practice of Oncology), edition 12. RISK FACTORS

12. Gallstone disease - Almost 90% of gallbladder cancer specimens contain stones incidence of gallbladder cancer in the population of patients with stones = 0.3% to 3% >3cm stones Porcelain Gallbladder incidence upto 25% stippled calcification of the mucosa> diffuse intramural calcification Gallbladder Polyps : >1cm 88% chance of malignancy >50yrs, PSC-0.8cm β-catenin.

13. Primary Sclerosing Cholangitis Chronic infection : Salmonella Typhi, H. pylori, H.bilis NOTE : Most epidemiologic data point to a significant relationship between chronic inflammation of the gallbladder and the development of neoplasia

14. Abnormal Pancreaticobiliary duct junction : Incidence- 2% Younger age K- ras Obesity Gallbladder wall thickening : CECT is the best modality for the evaluation. 

15.   Approach for gb wall thickening for an accurate diagnosis : Is the thickening focal or diffuse?  Is the diffuse thickening symmetrical or asymmetrical? The presence of intramural nodules. Mucosal enhancement pattern: intense inner layer enhancement with a weakly enhanced or unenhanced outer layer, seen in GB cancer. Secondary bile duct dilatation. Pericholecystic inflammation, adhesions Liver invasion and nodal involvement. Involvement of other organs.

16. PATHOLOGY

17. GB CA 1)Metaplastic 2)Non metaplastic A)Intestinal B)Pseudopyloric The intestinal type has a higher rate of carcinoma. The most important prognostic factor - stage at presentation

18. Site: Fundus-60% > Body-30%, > Neck of the gallbladder-10%. Tumors arising in the neck / Hartman pouch → infiltrate the cystic and common bile duct - clinically and radiographically indistinguishable from pCCAs .

19. GBCs- 1)Infiltrative,2)Nodular or 3)Papillary forms. Most common: 1) Infiltrative type - Cause thickening and induration of the gallbladder wall Spreads in subserosal plane. Tumor seeding into the peritoneal cavity occurs if Subserosal plane is violated during surgery Presence of the tumor is not recognized at the time of, cholecystectomy Advanced tumors → invade the liver → thick wall of tumor encasing the gallbladder. GROSS MORPHOLOGICAL TYPES

20. 2)Nodular or mass-forming GBCs - Early invasion through the gallbladder wall into the liver / neighboring structures. 3)Papillary carcinomas - Exhibit a polypoid or cauliflower-like appearance and fill the lumen of the gallbladder with only minimal invasion of the gallbladder wall

21. Spread Lymphatic metastasis-91% to 94%, Hematogenous metastasis -65% to 82%, and Peritoneal spread- 60% Hematogenous metastasis - due to invasion into small veins that extend directly from the gallbladder into the portal venous system, leading to hepatic metastases in segments IV and V of the liver) Distant metastasis-late ( High propensity for intra-abdominal recurrence after resection) The only common extra-abdominal site of metastasis is the lung.

22. Clinical Features And Diagnosis

23. Clinical features Often asymptomatic. Symptoms of Biliary colic or chronic cholecystitis. Diffuse abdominal pain of a more constant nature. Recent weight loss with right upper quadrant pain , elderly patient : high suspicion of GBCs. Jaundice : advanced or unresectable disease, poor prognostic sign. Rarely , duodenal or colonic obstruction, cholecysto -enteric fistula. Extra-abdominal metastasis, such as palpable mass Paraneoplastic syndromes like acanthosis nigricans.

24. Diagnosis Ultrasound whole abdomen : first investigation of choice, can show findings suggestive of GBCs , but not diagnostic. Abdominal CT scans : identify intraluminal polyps, gallbladder wall thickening, mass lesions, hepatic involvement and distant metastasis. MRI : biliary tree, vascular involvement and nodal involvement BLOOD IX : increase in ALP , total Bilirubin levels. TUMOR MARKERS: Serum CEA and CA 19.9 maybe elevated, but not diagnostic.

25. Cholangiography using ERCP or PTC : to plan the surgical resection by determining extent of ductal involvement. FDG-PET : low sensitivity for extra-hepatic disease. Tissue biopsy : controversial, risk of tumor seeding along the needle tract. Bile Cytology - by ERCP/PTC. Sensitivity-75%. EUS : sensitivity 92% and specificity 88% . useful for staging by assessing tumor wall invasion or distant nodal spread. DIAGNOSTIC LAPAROSCOPY

26. For patients in whom surgery is planned, a preoperative biopsy is contraindicated, as gallbladder cancer has a propensity for dissemination along needle tracts For patients in whom surgical exploration is contraindicated because of medical comorbidities or due to metastatic or unresectable disease, a percutaneous or endoscopic needle biopsy can be obtained to confirm the diagnosis. BIOPSY?

27. USG Mural thickening or calcification, A gallbladder mass greater than 1 cm in diameter Loss of the normal gallbladder wall–liver interface

28. STAGING

29. MANAGEMENT

30. Three common scenarios in which gallbladder cancer is discovered : (1) F ound on pathologic review of a cholecystectomy performed for presumed benign disease . (2) S uspected or diagnosed preoperatively, either resulting from a workup for symptoms attributable to the tumor or found incidentally . (3) It can be discovered intraoperatively, often on exploration for presumed cholecystitis.

31. Management Treatment of localized and locally advanced gallbladder cancer Treatment of unresectable gallbladder cancer Treatment of metastatic gallbladder cancer Incidental gallbladder cancer (IGBC)

32. Localised and locally advanced gbcs When GBCs is suspected, open cholecystectomy followed by frozen section if positive proceed for radical cholecystectomy. Surgery is the only potentially curative option for GBCs. For clinically T3 and T4 disease: Wedge resection of liver segment IVB and V Extrahepatic bile duct resection Portal lymph node dissection Resection of adjacent involved Organs.

33. IGBC “Incidental gallbladder cancer” (IGBC) - preoperatively unsuspected GBC diagnosed incidentally after cholecystectomy purely as a histopathological surprise. Incidence - 0.25–3.0% of patients undergoing Laparoscopic Cholecystectomy will be detected to harbor GBC. 2 clinical groups : a)Those detected during cholecystectomy b)Diagnosed histopathologically after cholecystectomy for presumed benign disease.

34. Majority - pT2/pT3 primaries. Commonest sites of residual disease- Liver bed and periportal LN Residual disease has been found to be the most relevant prognostic factor for survival in patients treated with curative resection. Radical re-resection or revision surgery for IGBC is termed as completion extended cholecystectomy or completion radical cholecystectomy. Timing of revision surgery is much debated. Generally, should be performed within 4–6 weeks from the index cholecystectomy once the post-operative inflammation settles.

35. Staging reassessment Reviewing the primary USG (ultrasonography) report. Discussion with the previous operating surgeon about specific intraoperative findings. Bile spillage Type of cholecystectomy (subtotal or total cholecystectomy), port used for GB extraction and use of bag for extraction, etc. should be enquired.

36. Complete local and metastatic workup for IGBC -Contrast-enhanced CT (CECT) of the abdomen, pelvis, and chest. -PET-CT: detects metastatic lesions in patients with suspected residual disease or with large periportal lymph nodes, suspicious aorto- caval nodes, or high CA19-9 levels.

37. T2 and beyond should undergo completion radical cholecystectomy. Routine bile duct excision - does not improve survival and may not necessarily improve lymph node yield. Major hepatectomy does not provide any survival benefit and increases morbidity as compared to partial/wedge resection of liver bed to negative margins. Excision of at least five nodes has been shown to improve survival and therefore at least 6 lymph nodes are recommended to be removed for adequate staging . Routine port site excision fails to reduce disease recurrence, does not improve survival.

38. Lymph node metastasis Regional lymph nodes of the gallbladder Cystic Pericholedochal , Posterior superior (posterosuperior) pancreaticoduodenal, Retroportal , Right celiac, Hepatic artery node groups. Number of positive lymph nodes and not location independently determines the prognosis after resection in patients with gallbladder carcinoma Sakata J, Shirai Y, Wakai T, Ajioka Y, Hatakeyama K. Number of positive lymph nodes independently determines the prognosis after resection in patients with gallbladder carcinoma. Ann Surg Oncol. 2010 Jul;17(7):1831-40. doi: 10.1245/s10434-009-0899-1. Epub 2010 Jan 15. PMID: 20077022.

39. Neoadjuvant and adjuvant therapy Recently published study by Patkar et al. on IGBC noted advantage of NACT in disease-free and overall survival in Stage III IGBC. Patients with locally advanced iGBC at presentation had superior OS when operated after neoadjuvant therapy [3-year estimated OS of 59.9% vs 32.3%, respectively ( p  = 0.001)]. Revision Surgery for Incidental Gallbladder Cancer—Challenging the Dogma: Ideal Timing and Real-World Applicability Shraddha Patkar MCh ,  Swapnil Patel MCh ,  Amit Gupta MCh , Anant Ramaswamy DM ,  Vikas Ostwal DM  &  Mahesh Goel MS   Annals of Surgical Oncology   volume 28 , pages6758–6766 (2021)

40. Proposed treatment algorithm of chemotherapy for advanced biliary tract cancer. GEM; gemcitabine, CDDP; cisplatin, FOLFOX; 5-fluorouracil + leucovorin + oxaliplatin, IDH; isocitrate dehydrogenase, FGFR; fibroblast growth factor receptor, MSI; microsatellite instability, NTRK; neurotrophic tyrosine receptor kinase .

41. Adjuvant therapy Chemotherapy : >pT1b , positive nodes, margin positive status.

42. CHEMORADIOTHERAPY Among patients undergoing potentially curative resection, postoperative external beam RT can diminish local recurrence rates. A feasibility study conducted by SWOG supports the use of capecitabine-based chemoradiotherapy in conjunction with   capecitabine  plus  gemcitabine .

43. FOR NACT- UK Abc-02 trial - cisplatin + gemcitabine = associated with a significant survival advantage without the addition of substantial toxicity. FOR ADJUVANT THERAPY : ACTICCA-01 : Now the standard of care in advanced disease is capecitabine , which is now the standard of care adjuvant drug

44. BILCAP TRIAL : IS CAPECITABINE THE WINNER IN THE ADJUVANT THERAPY OF BILIARY TRACT CANCER? Dose-1250 mg/m 2  twice daily on days 1 to 14 every 21 days. Overall survival- 14.7 months. Conclusion - Capecitabine should be considered the new standard of care in resected biliary cancer

45. Prognostic factors   Tumor invasion depth as indicated by the pathologic tumor (T) stage, Lymph node metastases, Serum levels of the tumor marker cancer antigen 19-9 (CA 19-9), status of the surgical margins Tumor grade, and presence of lymphovascular and perineural invasion.

46. Patterns of disease recurrence Margin-positive resections : locoregional recurrences predominate Main patterns of recurrence were : Retroperitoneal lymph nodes (28 percent) Intrahepatic (22 percent) Locoregional recurrence (hilum, bilioenteric anastomosis, hepatic resection margin; 20.9 percent) Peritoneum, lung, bone, and abdominal wall ( totaling 15 percent) Other distant lymph nodes (14 percent) Risk factors influencing recurrence, patterns of recurrence, and the efficacy of adjuvant therapy after radical resection for gallbladder carcinoma. AU Kim WS, Choi DW, You DD, Ho CY, Heo JS, Choi SH SO J Gastrointest Surg. 2010 Apr;14(4):679-87. Epub 2010 Jan 22. 

47. UNRESECTABLE GBCS Biopsy from the GB mass or wall thickening. Jaundice: Biliary drainage Consider for Neoadjuvant therapy. Advanced GBC has a 1 year survival rate of <1%. The aggressive nature and dismal prognosis of the advanced unresectable cancer should be considered before initiating treatment.

48. TMH criteria (for Locally advanced/Borderline Resectable GBC used as an indication for Neoadjuvant Chemotherapy) Tumour (T3–T4 tumours) – Contiguous liver involvement > 2 cm Involvement of bile duct causing obstructive jaundice (Type I/II block on MRCP/ERCP/PTBD) Radiological/Endoscopic involvement of antropyloric region of stomach, duodenum, hepatic flexure of colon or small intestine

49. Node (N1 station) Radiological suspicion : Hepatic artery (Station 8), Hepatoduodenal ligament (Station12), Retro pancreatic/ retroduodenal (Station 13) Size > 1 cm in short axis, round in shape, and heterogenous enhancement on CT/PET scan.

50. Vascular (T4 tumours) : Impingement/involvement(<180 degree) of one or more following blood vessels. Common Hepatic Artery and Right & Left Hepatic artery Main Portal vein and Right & Left Portal vein For incidental GBC: Residual/Recurrent mass in GB fossa/liver bed N1 nodes as per nodal criteria. Involvement of bile duct causing OJ (Type I/II Block)

51. Metastatic GBCS Consider for biopsy. Palliative chemotherapy - Locoregionally advanced, Unresectable GBC / those with Distant metastatic disease who are able to tolerate it. Clinical trials enrollment .

52. Molecularly targeted therapy . Deficient mismatch repair:   Pembrolizumab. PD-L1 overexpression: Nivolumab . VEGF-   Bevacizumab .

53. Topaz-1 trial: Durvalumab +Gemcitabine +Cisplatin Could Become New First-Line Standard of Care for Advanced Biliary Tract Cancer. Oh D-Y, He AR, Qin S, et al. A phase 3 randomized, double-blind, placebo-controlled study of durvalumab in combination with gemcitabine plus cisplatin (GemCis) in patients (pts) with advanced biliary tract cancer (BTC): TOPAZ-1 (abstract). J Clin Oncol 2022.40.4_suppl.378.

54. Palliative care Prevent bowel and biliary obstruction. Relieve of pain. End stage care and support.

55. SURVIVAL T1a- T1b : complete resection with negative margins affords 90-100% 5 year survival. T2 depending on nodal status and resection margins, 5 year survival is approximately 20% to 60%. T3 is <20%. T4 measured in months. Overall patients with advanced disease survival is less than 15%.

56. Follow-up Clinical examination every 3-6 months and then 6-12 months upto 5 years. Imaging every 3-6 months for 2 years, then every 6-12 months upto 5 years. Consider CEA and CA19.9 as clinically indicated.

57. Conclusion GBCs is highly aggressive and highly fatal malignancy. The poor prognosis is thought to be related to advanced stage at diagnosis, which is due both to the anatomic position of the gallbladder and to the vagueness and nonspecificity of symptoms. Surgery is the only potentially curative modality for patients with GBC. Only a minority of patients are eligible for curative-intent surgery because of disease extent.  For the remainder, treatment is palliative in nature.

58. REFERENCES: Devita 12 th edition Sabiston textbook of surgery 21 st edition Bailey and Love Short practice of Surgery 27 th edition. Blumgart’s Surgery of the Liver, Biliary Tract, and Pancreas . Edition 6

59. THANK YOU